Artificial method for modifying the reproductive cycle in animals

ABSTRACT

A method for changing and resetting the starting time of the estrus or reproductive cycle in female animals (e.g. a cow) including the steps of inserting a mechanical device therein, engaging the device with the reproductive tract wall to prevent expulsion by the animal straining and exerting pressure sufficient to alter the cross-sectional configuration of the tract wall for a substantial period of time. This pressure causes alteration or stimulation of the reproductive or estrus cycle regulatory mechanism of the animal to reset the beginning of the reproductive cycle, and under certain conditions, to cause a shortening of the cycle. A typical device includes a number of radially projecting resilient hoops.

United States Patent [191 Dickinson, III et al.

1 ARTIFICIAL METHOD FOR MODIFYING THE REPRODUCTIVE CYCLE IN ANIMALS [75]Inventors: Ben W. O. Dickinson, III, San

Francisco; Robert W. Dickinson, San Rafael, both of Calif.; Cecil R.Miller, Westchester, Pa.

[73] Assignees: Smith, Kline & French Laboratories,

Philadelphia, Pa. by said Miller; Agrophysics, Inc., San Francisco,Calif. by said Ben W. O. Dickinson, I11 and Robert W. Dickinson [22]Filed: Jan. 22, 1971 [21] Appl. No.: 108,922

[52] US. Cl 128/1 R, 128/130, 128/341 [51] Int. Cl A61b 19/00 [58] Fieldof Search 128/1 R, 2 R, 3, 127, 130,

[11] 3,811,424 May 21, 1974 3/1970 Hamilton l28/345'X 2/1969Robinson.... 128/130 OTHER PUBLICATIONS Robinson The Control of theOvarian Cycle in the Sheep 1967, Sydney Univ. Press, pp. 115, 243-244relied on [5 7] ABSTRACT A method for changing and resetting thestarting time of the estrus or reproductive cycle in female animals(e.g. a cow) including the steps of inserting a mechan- 1 ical devicetherein, engaging the device withthe reproductive tract wall to preventexpulsion by the animal straining and exerting pressure sufficient toalter the cross-sectional configuration of the tract wall for asubstantial period of time. This pressure causes alteration orstimulation of the reproductive or estrus cycle [5 6] References C'tedregulatory mechanism of the animal to reset the begin- UNITED STATESPATENTS ning of the reproductive cycle, and under certain con- 3,192,9287/1965 Horton 128/341 ditions, to cause a shortening of, the cycle. Atypical 430,137 6/1890 Meddick l28/343 device includes a number ofradially projecting resil 3,297,020 l/l967 Mathiesen 128/2 R iem boom328,553 lO/l885 Warmoth.... 128/127 T" 4,825 10/1846 Merriman 128/127 7Claims, 1 Drawing Figure a 0 M I, ,I /7 /8 /4 C 6% 3 4 /2 --..f###/4%ARTIFICIAL METHOD FOR MODIFYING THE REPRODUCTIVE CYCLE IN ANIMALSBACKGROUND OF THE INVENTION A complex information transport network ofinterconnected neutral and hormonal factors controls the estrus orreproductive cycle in female animals, particularly of the type having atubular reproductive tract including an ovary (e.g. humans, cows,chickens, dogs, horses, hogs, and the like). In a cow, typical of thatgroup, growth of an ovarian follicle begins under the influence offollicle-stimulating hormone (FSH) from the adenohypophysis. Estrogenfrom the developing follicle appears to be part of a neurohormonalfeedback. Gonadotropin secretions in response to these neurohormonalinputs trigger the rapid growth and maturation of a follicle to reach aGraafian follicle state. Ovulation of the mature follicle appears tooccur in response to the pituitary gonadotropin, luteinizing hormone(LH), which reaches a peak level just prior to ovulation. Immediatelyafter ovulation the corpus luteumm forms at the site of ovulation andproduces an increased amount of progesterone which acts as a hormonalfeedback. In the absence of fertilization, the corpus luteum regressesand the production of progesterone reaches minimal levels. As theprogesterone output from the ovary is reduced, the output ofgonadotropin from the adenohypophysis again begins to increase, thegrowth of another ovarian follicle will be stimulated. Thus, thetime-phase combination of neutral and hormonal information transportsand feedbacks produces the normal estrus or reproductive cycleinitiation and length of cycle regulation.

Implanted capsules or feed additives of drugs, usually containingprogestogens, the removalor stopping of which permits triggering ofarapid ovulation, are unsatisfactory because of high cost, poorsynchronization, bad side-effects and poor fertility results when theovulation retarding drug is removed or stopped.

Intrauterine devices of conventional construction are, in manyinstances, spontaneously expelled from the reproductive tract by theanimal. Furthermore, the devices open the cervix of the cow over anextended period of time to expose the normally asceptic uterus whichcould potentially cause infection to the same from external sources.

SUMMARY OF THE INVENTION AND OBJECTS It is an object of the presentinvention to provide a method for changing or resetting all or acombination of the follicular, luteal or ovulation phases of the estrusor reproductive cycle in animalsof the type having a tubularreproductive tract with an ovary which overcomes the aforementioneddisadvantages of the prior art.

It is another object of the invention to use a device for changing orresetting the follicular, luteal or ovulation phases of a females estrusor reproductive cycle by stimulation of endogenous chemicals rather thanimplantation or feed addition of exogenous chemicals.

It is a further object of the invention to accomplish the above purposeutilizing only a mechanical device.

It is an additional object of the invention to provide a method fortemporarily anchoring the above mechanical device in the animalsreproductive tract.

It is another object of the invention to provide a method for causingovulation of an animal.

It is another object of the invention to provide a method forcontraception by resetting the follicular, luteal or ovulation phases ofthe reproductive or estrus cycle.

In accordance with the above objects, a method for mechanically changingor resetting the starting time of the estrus or reproductive cycle inanimals of the type having a tubular reproductive tract with an ovary isprovided by a method of inserting into the animals reproductive tract adevice such as the type described in the application entitled Device forInsertion into the Reproductive Tract and Method of Using the Same inthe names of Ben Wade Oakes Dickinson III and Robert Wayne Dickinson,Ser. No. 108,889, filed Jan. 22, 1971. A device is inserted into theanimals reproductive tract wherein it is engaged with the tractwall toretain the same within the tract for a substantial period of time bypreventing expulsion of the device from the tract by the animal. It hasbeen discovered that exerting sufficient pressure by the device to alterthe crosssectional configuration of the tract wall from the normalcondition for a sufficient period of time causes adequate stimulation ofthe estrus or reproductive cycle neutral-hormonal regulatory mechanismsof the animal to change or reset the beginning of the reproductivecycle. For clarity of description, the following discussion will relateto the cow, which has a tubular reproductive tract including a uterusopening through a cervix into the vagina. It should be understood that,unless otherwise specified, the method may also be applied to otheranimals having a tubular reproductive tract including an ovary such ashumans, horses, hogs, dogs and chickens. In the cow, the desirableposition for tract engagement is within the vagina, anterior to thesphincter-like muscle or constriction.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. I is a cross-sectional view of atypical mechanical stimulating device inserted into the vagina of ananimal.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In order to change orreset the follicular, luteal or ovulation phases (of) the estrus orreproductive cycle, a device of the type generally described in theaforementioned application A-26l30 is insertedinto the tubularreproductive tract. A typical device which may be employed for thepresent invention, as illustrated in FIG. 1, is inserted into the vaginaof a cow. This device is described as a vaginal anchor assembly inapplication Ser. No. 108,889 illustrated prior to insertion as FIGS. 20and 22 and after insertion in FIG. 23 in that case. Briefly describingFIG. I, strands 10 form an umbrellalike shape with posterior concavityof the initial rosette-like pattern as a result of partial collapseduring insertion into the vagina. It is seen that the strands projectinto folds of the vaginal wall in intermeshing fashion. The anteriorends of strands 10 are fixedly secured to mounting ring 11 which, inturn, is carried by housing 12 as by forming the ring of a resilientmaterial and sliding the same over the housing to form a tight fit.The'posterior mounting ring 13 is slideably carried by housing 12 and ismaintained in the illustrated position by means of plugs 14 extendingthrough rings 13 and seated in accommodating recesses of housing 12.Plug 14 may be formed of a slowly disintegrable material such as watersoluble cross-linked polyethylene oxide or slowly vaporizableparadichlorobenzene as described in application A-26l 30. It is notedthat the periphery of the umbrella abutts against the posterior side ofthe sphincter-like constriction or muscle in the vagina denoted as M. Itis an important aspect of the present invention that the anchoringportion of the device which engages the vaginal wall of the cow remainsto the anterior of the sphincter-like constriction or muscle to providethe anchor with a backing for a secure position. Furthermore, if theanchor projects into the vestibule of the vagina to the posterior of thesphincter-like muscle, because the animal is particularly sensitive toforeign bodies in this region, she would begin a natural strainingmovement which would urge the assembly posteriorly for expulsion.

Referring again to FIG. 1, the anterior portion of the device includes aclamping ring 16 which slides over and compresses against the projectingannulus of the cow's cervix, denoted as C. Clamping ring 16 is connectedto housing 12 in a flexible manner by a series of spaced apart elongatedstrands 17 fixedly secured at one end to the clamping ring and at theother end to mounting ring 18 which, in turn, is fixedly secured to andcarried by housing 12. Strands l7 perform' the function ofa flexiblecervical follower which allows for relative movement of the device withrespect to the cervix to accommodate movement of the reproductive tractand particularly the cervix as during defecation. In addition, strands17 are under a certain amount of compression so that the vagina isstretched axially between the cervix and muscle ,M.

The above device may be removed manually after it has been inserted forthe desired amount of time or the device may be provided with aself-actuating removal mechanism which provides for an automatic changein shape or characteristics which engenders removal of the device; Inthe former or manual technique, the above-described device may beremoved by manually withdrawing it without alteration or by sliding ring13 anteriorly to collapse loops so that the outward projection of theanchor is reduced or eliminated. In the automatic technique, the plug 14may disintegrate after a predetermined period of time. Thereafter, thespringlike compression of strands 10 in a hoop-like configuration willurge ring 14 posteriorly to project into the sensitive vestibule on theposterior side of the sphincterlike muscle. This rearward movementcauses the collapse of the outward projection of the anchor as with themanual assembly except that the animals natural straining movement toeject a foreign body will urge the anchor assembly, along with theremainder of the device, to be expelled from the animal.

In accordance with the invention, radial pressure suf ficient to alterthe cross-sectional configuration of the tract wall from the normalcondition is exerted by the above anchor assembly or other assembliesillustrated in application Ser. No. [08,889 or any other device whichperforms that function. Additional or axial stimulation is provided bythe compressed follower strands 17. It should be understood that thelatter type of stimulation normally is not essential to perform thedesired results.

An effective anchor may be formed in which the primary stimulation isaxial rather than radial. For exampie, the anchor may include a cervicalfollower retained at the anterior of the device by a cervical ring incombination with an element which projects from the anchor into a recesswhich exists in the aforementioned vaginal sphincter-like constrictionto retain the posterior side of the anchor.

For ready insertion of the device into the cows vagina, strands 10 maybe compressed into the closed hand of a technician or into a speculum asin the form of a hollow tube, not shown, which is withdrawn afterinsertion of the device for subsequent outward projection of strands 10.in mature animals, a device within a speculum of 2.5-3.5 inches diametercan readily be passed between the pin bones into the vulva and throughthe posterior vaginal sphincter-like constriction into the vagina of thecow. After the device is to the anterior side of constriction M, it canexpand radially within the vagina of a mature animal without causingundue stress or related behavioral patterns because the animal, such asa cow, is not highly sensitive to the presence of a foreign object inthis region of the vagina. By extending the anchor for engagement withthe folds of the vagina as illustrated in FIG. 1, the device may beretained within the tract for a substantial period of time since it isengaged without local irritation to the epithalium in portions of thevaginal wall in a manner to inhibit spontaneous expulsion.

In animals of the type having a uterus opening through a cervix into avagina which require extensive stimulation, the aforementioned vaginalstimulation may be augmented by cervical or uterine stimulation such asby means illustrated in FIG. 2. The cervical stimulator is illustratedin the form ofa helical or other shaped element 20 mounted at onegenerally straight end in a retaining sleeve 21 which, in turn, isretained within a cervical ring 22 by means of radial spokes 23 topermit bypass of the spokes by fluids emitted from the cervix. The otherend of element 20 is attached to the uterine stimulator illustrated asan enlarged helical or other shaped element 23 by means of a generallystraight connecting link 24 which does not disturb the normally tightposterior os, denoted O, of the cervix. It should be understood thatneither the uterine nor cervical stimulator is capable of being anchoredin place for substantial periods of time to prevent spontaneousexpulsion in the absence of the anchoring device described herein or ofthe alternative ones described in application A-26l30. It is noted thatthe uterine and cervical stimulators distend the uterus and the cervix,respectively, to provide the desired amount of stimulation. Thesestimulators are only required in those exceptional cases where morestimulation than can be provided by the vaginal anchor is desired for aparticular purpose.

Protective measures are desirable in accordance with the presentinvention. Exerted pressure should be insufficient to cause extensivecutting or irritation of the tract wall or or pressure necrosis in thearea of the engaged tract wall or to cause overstimulation ofreproductive cycle regulatory mechanisms to thereby prevent undesirableside effects. Furthermore, reproductive tract fluids should bechannelled past the area of engagement to minimize fluid stagnation andresultant irritation or infection evolving from growth of microorganismsin the stagnant retained fluid. This is accomplished in the bypass ofthe spaced-apart hoops 10. In addition, housing 12 may be hollow andopen-ended to provide an open passageway for fluids. Also, strandsshould be no more rigid than necessary to provide adequate stimulationand to prevent expulsion by animal straining or natural movement. Nylonor plastic strands of l/l6-3/32 inch OD have been found to have theproper amount of flexibility for this purpose. Nylon, polyethylene andother plastics which are biologically compatible materials may be usedto construct the device for extended retention in the vaginal lumenwithout causing irritation.

By way of example, in the cow an anchor of the type illustrated in FIG.1 having an outer diameter of seven inches and with 12 to 16 plasticstrands has been found to be sufficient stimulator and retainer forpurposes of the present invention. Of course, the addition of theanterior anchor portion which provides axial stimulation would provideadditional stimulating effects, if desired.

It has been found that insertion of devices of the foregoing type intothe vagina of a cow engages the vaginal wall for retention in the tractby preventing expulsion by the animal. Furthermore, the radial pressureexerted, which is sufficient to alter the cross-sectional configurationof the tract wall from the normal condition, if applied for a sufficientperiod of time, causes adequate stimulation of the estrus orreproductive cycle regulatory mechanisms of the animal to change orreset initiation of follicular, luteal or ovulation phases of theanimals reproductive or estrus cycle. When the device is in place for aperiod greater than about one-half hour, cervical mucus flows andopening of the cervix almost immediately follows. This effect isinferred to be generally associated with an increase in estrogen whichis normally precursive of behavioral estrus during a normalnon-artifically stimulated reproductive cycle. Removal of the deviceafter cervical mucus fiow begins results in an in-phase rise in aboutone day of progesterone, estradiol, estrone and an LH pea n about 1 saw.with amises ffitl result. H92? ever, neither stimulated standing heatnor associated ovulation occur within one or two days after mucus flow,as would be expected in a normal estrus or reproductive cycle.

The continued vaginal implacement of the device beyond a few hourscauses a soft spot or small follicle to develop on the ovary in aboutone to three days. This soft spot may mature into a normal follicle inabout five days when the device remains in place.

Continued vaginal implacement of the device beyond two to three daysproduced the unexpected result that the udders of milking cows weresubstantially fuller at milking than they would normally be at that timein the reproductive cycle. It may be inferred from this observation thatsuch continued implacement causes accumulation of oxytocin, possibly inthe posterior pituitary, with aconsequent higher continual release rateof oxytocin than without the device in place. Such high oxytocin releaserate is known to result in a fuller udder.

When the device is removed, there is an immediate and dramatic increasein uterine tone which is inferred to indicate a rapid release ofa poolof oxytocin, probably from the posterior pituitary.

By leaving the device implaced in the vagina for an indefinite period oftime and in excess of, for example, 20 days, the beginning of thereproductive cycle has been artificially changed or reset. Thisregulation of the timing of the cycle may be employed for contraceptionas in human beings by increasing the effectiveness of the rythym methodof contraception.

The frequency of this reduction in the timing of the reproductive cyclecoupled with the resetting of the beginning of the cycle is an extremelyefiective aid in artificial or natural insemination. These longimplacement time devices are generally of a lower level of stimulation,i.e. smaller in size, and provide less radial pressure than those usedin the combined implacement/removal methodology.

Another effective application of the foregoing observations is toimplace the device in the animal for a certain minimum time (e.g. atleast six to seven days in cows). Thereafter, the device may be removedwith the knowledge that at a subsequent time thereafter the animal maybe inseminated.

It has been found that neither stimulated standing heat nor ovulationalways occur while the device is still implaced. These lacking effectsare believed to be the result of an improper balance of hormones.

Removal of the device after a certain minimum time of continuousstimulation may results in standing heat and ovulation but it is notclearly defined from animal to animal. The high occurrence of anapparently nor-' mal ovulation with precursor standing heat probablyindicates the existence of a proper balance of hormones.

Insertion of a mechanical device of the above general type stimulatesendogenous chemicals to modify the estrus or reproductive cycle producesa relatively normal condition with minimal side effects to the animal.This is in marked contrast to the substantial deleterious side effectswhich result in the use of exogenous chemicals as with implants or feedadditives.

Although the foregoing discussion relates primarily to insertion ofadevice in the vagina ofa cow, it should be understood that the method isapplicable to animals of the type having similar stimulated responsemechanisms and also having a tubular reproductive tract includingovaries. Of course, to accommodate different sizes and shapes of theanimals reproductive tracts and the different cycle times, the foregoingsizes and shapes of the device and timing for adequate stimulation wouldbe modified.

We claim:

1. In a method for inducing early follicle growth and estrus in aprepuberal animal of the type having a vagina terminating at theposterior end in a normally closed vulva and at the anterior end at thecervix of the uterus, said vagina having an annular sphincter musclebetween the anterior and posterior ends of the same, utilizing a deviceincluding mounting means with an annular surface and spaced-apartyieldable means carried by the mounting means and projecting axially ofthe annular surface and being disposed circumferentially about an axisgenerally coincident with the axis of the annular surface, saidspaced-apart yieldable means being capable of being compressed to a sizeso that the device can be readily inserted through the vulva into thevagina, said device being of a length so that it can be disposed betweenthe cervix and the sphincter muscle, the method comprising the steps ofinserting the device through the vulva into the animal's vagina into aposition anterior of said vaginal sphincter muscle while thespaced-apart yieldable means is compressed, permitting the spaced-apartyieldable means to expand into contact with the vaginal wall to expandthe vaginal wall beyond its normal condition to thereby retain thedevice within the vagina and preventing expulsion of the device from thevagina by the animal while permitting the vulva to remain closed andpermitting said device to remain in the vagina for a period greater thanone day so that pressure is exerted on the vaginal wall for said periodto induce early follicle growth and estrus.

2. A method as in claim 1 in which the pressure exerted by the device onthe vaginal wall is insufficient to cause extensive abrasion of thevaginal wall or pressure necrosis of the vaginal wall.

3. A method as in claim 1 wherein the device is formed to permit flow ofreproductive tract fluids past the device in the vagina.

4. A method as in claim 1 in which the device is retained in the vaginafor at least five days.

5. A method as in claim 1 together with the step of removing the devicewhen estrus has commenced.

6. A method as in claim 1 in which the animal is of a type having acervix with a lip which projects into the vagina and in which the deviceis positioned so that the mounting means engages said lip to assistretention of said device in the vagina and to stimulate the cervix.

7. in a method for inducing early follicle growth and estrus in aprepurberal animal in which the reproductive tract is characterized inthat it is defined by a foldcontaining wall forming an elongatesheath-like tubular passage with its anterior end leading from thecervix of the uterus and with its posterior end terminating in anormally closed vulva and which has an annular sphincter muscle betweenthe anterior and posterior ends and in which the device is characterizedby having mounting means with the mounting means including an annularportion, spaced-apart yieldable means carried by the mounting means andprojecting axially of the mounting means and also extendingcircumferentially about an axis generally coincident with the axis ofthe annular portion, said yieldable means being deformable from a normalexpanded condition to a depressed condition, said yieldable meansin saiddepressed condition being of a size so that it can be readily insertedthrough the vulva into the passage of the animal, said device having adimension extending longitudinally along the passage which is such thatthe device can be disposed between the cervix and the sphincter muscleto permit the vulva to remain in its normally closed condition when thedevice is between said sphincter muscle and the cervix, the methodcomprising the steps of compressing the yieldable means and insertingthe device through the vulva into the passage so that the device ispositioned between the cervix and the sphincter muscle,- permitting theyieldable means to expand into engagement with the fold-containing wallto cause expansion of the fold-containing wall beyond its normalcondition so that the device will be retained within the passage tothereby inhibit explusion of the device from the passage by the animal,and permitting said yieldable means to exert pressure against thefold-containing wall for a period of at least one day to causestimulation of the animal in the vicinity of the fold-like wall tothereby induce early-follicle growth and estrus in the animal andremoving the device from said passage after estrus has been induced.

II I I. I!

1. In a method for inducing early follicle growth and estrus in aprepuberal animal of the type having a vagina terminating at theposterior end in a normally closed vulva and at the anterior end at thecervix of the uterus, said vagina having an annular sphincter musclebetween the anterior and posterior ends of the same, utilizing a deviceincluding mounting means with an annular surface and spaced-apartyieldable means carried by the mounting means and projecting axially ofthe annular surface and being disposed circumferentially about an axisgenerally coincident with the axis of the annular surface, saidspaced-apart yieldable means being capable of being compressed to a sizeso that the device can be readily inserted through the vulva into thevagina, said device being of a length so that it can be disposed betweenthe cervix and the sphincter muscle, the method comprising the steps ofinserting the device through the vulva into the animal''s vagina into aposition anterior of said vaginal sphincter muscle while thespaced-apart yieldable means is compressed, permitting the spaced-apartyieldable means to expand into contact with the vaginal wall to expandthe vaginal wall beyond its normal condition to thereby retain thedevice within the vagina and preventing expulsion of the device from thevagina by the animal while permitting the vulva to remain closed andpermitting said device to remain in the vagina for a period greater thanone day so that pressure is exerted on the vaginal wall for said periodto induce early follicle growth and estrus.
 2. A method as in claim 1 inwhich the pressure exerted by the device on the vaginal wall isinsufficient to cause extensive abrasion of the vaginal wall or pressurenecrosis of the vaginal wall.
 3. A method as in claim 1 wherein thedevice is formed to permit flow of reproductive tract fluids past thedevice in the vagina.
 4. A method as in claim 1 in which the device isretained in the vagina for at least five days.
 5. A method as in claim 1together with the step of removing the device when estrus has commenced.6. A method as in claim 1 in which the animal is of a type having acervix with a lip which projects into the vagina and in which the deviceis positioned so that the mounting means engages said lip to assistretention of said device in the vagina and to stimulate the cervix. 7.In a method for inducing early follicle growth and estrus in aprepurberal animal in which the reproductive tract is characterized inthat it is defined by a fold-containing wall forming an elongatesheath-like tubular passage with its anterior end leading from thecervix of the uterus and with its posterior end terminating in Anormally closed vulva and which has an annular sphincter muscle betweenthe anterior and posterior ends and in which the device is characterizedby having mounting means with the mounting means including an annularportion, spaced-apart yieldable means carried by the mounting means andprojecting axially of the mounting means and also extendingcircumferentially about an axis generally coincident with the axis ofthe annular portion, said yieldable means being deformable from a normalexpanded condition to a depressed condition, said yieldable means insaid depressed condition being of a size so that it can be readilyinserted through the vulva into the passage of the animal, said devicehaving a dimension extending longitudinally along the passage which issuch that the device can be disposed between the cervix and thesphincter muscle to permit the vulva to remain in its normally closedcondition when the device is between said sphincter muscle and thecervix, the method comprising the steps of compressing the yieldablemeans and inserting the device through the vulva into the passage sothat the device is positioned between the cervix and the sphinctermuscle, permitting the yieldable means to expand into engagement withthe fold-containing wall to cause expansion of the fold-containing wallbeyond its normal condition so that the device will be retained withinthe passage to thereby inhibit explusion of the device from the passageby the animal, and permitting said yieldable means to exert pressureagainst the fold-containing wall for a period of at least one day tocause stimulation of the animal in the vicinity of the fold-like wall tothereby induce early follicle growth and estrus in the animal andremoving the device from said passage after estrus has been induced.